The present invention relates to a novel heterocyclic compound and a pharmaceutically acceptable salt thereof, which have a hypoglycemic action, a blood hypolipidemic action, an insulin resistance-improving action or a PPAR (peroxisome proliferator-activated receptor)-activating action. The present invention also relates to a pharmaceutical composition comprising the above-mentioned novel heterocyclic compound or a pharmaceutically acceptable salt thereof. Furthermore, the present invention relates to a hypoglycemic agent, a hypolipidemic agent, an insulin resistance improver, a therapeutic agent of diabetes, an anti-diabetic complication agent (i.e., a therapeutic agent of diabetic complication), a glucose tolerance improver, an anti-atherosclerosis agent, an anti-obesity agent, an antiinflammatory agent, an agent for the prophylaxis or treatment of PPAR-mediated disease and an agent for the prophylaxis or treatment of syndrome X, all of which comprising the above-mentioned novel heterocyclic compound or a pharmaceutically acceptable salt thereof.
As a therapeutic agent of diabetes, biguanide compounds having, as a main action, an inhibitory action on glucose absorption via the intestinal tract and on glucose release from the liver, sulfonylurea compounds having an accelerating action on insulin secretion as a main action, insulin and the like have been employed. However, biguanide compounds cause lactic acidosis, and sulfonylurea compounds sometimes cause serious hypoglycemia due to their strong hypoglycemic action. Therefore, a due care should be given when in use of these compounds. In recent years, there have been active researches and developments of a therapeutic agent of diabetes, which is free of these defects, with the consequence that various compounds having an insulin resistance-improving action have been found.
The insulin resistance is important as a cause of non-insulin dependent diabetes mellitus (NIDDM), along with decrease in the insulin secretion. Therefore, the development of a pharmaceutical agent that improves insulin resistance has been desired. Various thiazolidine compounds are known as the agent capable of improving the insulin resistance. As these compounds, for example, 5-[4-[(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)methoxy]benzyl]-2,4-thiazolidinedione (general name: troglitazone) is described in JP-B-2-31079, 5-[[4-[2-(5-ethyl-pyridin-2-yl)ethoxy]phenyl]methyl]-2,4-thiazolidinedione (general name: pioglitazone) is described in JP-B-5-66956, and 5-[[4-[2-[N-methyl-N-(pyridin-2-yl)amino]ethoxy]phenyl]methyl]-2,4-thiazolidinedione (general name: rosiglitazone) is described in JP-A-1-131169.
It is therefore an object of the present invention to provide a compound having a hypoglycemic action, a blood hypolipidemic action, an insulin resistance-improving action and a PPAR activating action, which has a structure completely different from that of conventional compounds, thereby to increase the diversity in and to broaden the range of selection from hypoglycemic agents, hypolipidemic agents, insulin resistance improvers, therapeutic agents of diabetes, therapeutic agents of diabetic complications, glucose tolerance improvers, anti-atherosclerosis agents, anti-obesity agents, antiinflammatory agents, agents for the prophylaxis or treatment of PPAR-mediated disease and agents for the prophylaxis or treatment of syndrome X.
The present inventors have conducted intensive studies in an attempt to solve the above-mentione problems and found that a heterocyclic compound having a novel structure of the formula [I] 
wherein
R1 is hydrogen atom or lower alkyl,
R2 is hydrogen atom, alkyl optionally having a substituent, cycloalkyl, cycloalkylalkyl, aryl optionally having a substituent, arylalkyl optionally having a substituent, alkenyl optionally having a substituent, alkynyl optionally having a substituent, heterocyclic alkyl optionally having a substituent or xe2x80x94COR4 
wherein R4 is hydrogen atom, alkyl optionally having a substituent, aryl optionally having a substituent, alkenyl optionally having a substituent, arylalkyl optionally having a substituent or heterocyclic residue optionally having a substituent,
R3 is hydrogen atom, lower alkyl or lower alkoxy,
A is a single bond or  greater than Nxe2x80x94R5 wherein R5 is hydrogen atom or lower alkyl,
B is lower alkylene, and
Y is aryl optionally having a substituent or an aromatic heterocyclic residue optionally having a substituent
and a pharmaceutically acceptable salt thereof have a hypoglycemic action, a blood hypolipidemic action, an insulin resistance-improving action and a PPAR activating action, which resulted in the completion of the invention.
Accordingly, the present invention relates to the following.
[1] A heterocyclic compound of the formula [I] 
wherein
R1 is hydrogen atom or lower alkyl,
R2 is hydrogen atom, alkyl optionally having a substituent, cycloalkyl, cycloalkylalkyl, aryl optionally having a substituent, arylalkyl optionally having a substituent, alkenyl optionally having a substituent, alkynyl optionally having a substituent, heterocyclic alkyl optionally having a substituent or xe2x80x94COR4 
wherein R4 is hydrogen atom, alkyl optionally having a substituent, aryl optionally having a substituent, alkenyl optionally having a substituent, arylalkyl optionally having a substituent or heterocyclic residue optionally having a substituent
R3 is hydrogen atom, lower alkyl or lower alkoxy,
A is a single bond or  greater than Nxe2x80x94R5 wherein R5 is hydrogen atom or lower alkyl,
B is lower alkylene, and
Y is aryl optionally having a substituent or an aromatic heterocyclic residue optionally having a substituent (hereinafter to be referred to as
heterocyclic compound [I]), and a pharmaceutically acceptable salt thereof;
[2] the heterocyclic compound of the above-mentioned [1] wherein, in the formula [I],
R1 is hydrogen atom or lower alkyl,
R2 is hydrogen atom, alkyl optionally having a substituent, cycloalkyl, cycloalkylalkyl, aryl optionally having a substituent, arylalkyl optionally having a substituent or xe2x80x94COR4 wherein R4 is hydrogen atom, alkyl optionally having a substituent, aryl optionally having a substituent or arylalkyl optionally having a substituent,
R3 is hydrogen atom, lower alkyl or lower alkoxy,
A is a single bond or  greater than Nxe2x80x94R5 wherein R5 is hydrogen atom or lower alkyl,
B is lower alkylene, and
Y is aryl optionally having a substituent or an aromatic heterocyclic residue optionally having a substituent, and a pharmaceutically acceptable salt thereof;
[3] the heterocyclic compound of the above-mentioned [1] wherein, in the formula [I],
R1 is hydrogen atom or lower alkyl,
R2 is hydrogen atom, alkyl, cycloalkylalkyl, arylalkyl optionally having a substituent, alkenyl, alkynyl, heterocyclic alkyl or xe2x80x94COR4 wherein R4 is alkyl, alkenyl or aryl,
R3 is hydrogen atom or lower alkoxy,
A is a single bond or  greater than Nxe2x80x94R5 wherein R5 is lower alkyl,
B is lower alkylene, and
Y is aryl or an aromatic heterocyclic residue optionally having a substituent,
and a pharmaceutically acceptable salt thereof;
[4] the heterocyclic compound of the above-mentioned [1] wherein, in the formula [I],
R1 is hydrogen atom or lower alkyl,
R2 is hydrogen atom, alkyl, cycloalkylalkyl, arylalkyl optionally having a substituent or xe2x80x94COR4 wherein R4 is alkyl or aryl,
R3 is hydrogen atom,
A is a single bond or  greater than Nxe2x80x94R5 wherein R5 is lower alkyl,
B is lower alkylene, and
Y is an aromatic heterocyclic residue optionally having a substituent,
and a pharmaceutically acceptable salt thereof;
[5] the heterocyclic compound of the above-mentioned [1] wherein, in the formula [I],
Yxe2x80x94Axe2x80x94 is 
wherein
RA is isopropyl or tert-butyl,
RB is isopropyl or tert-butyl,
RC is isopropyl, tert-butyl, phenyl, thiophen-2-yl, 2-methylpropenyl, 3-butenyl, cyclopropyl, 1-butenyl or 2,2-dimethylpropyl, and a pharmaceutically acceptable salt thereof;
[6] the heterocyclic compound of the above-mentioned [1] wherein, in the formula [I],
Yxe2x80x94Axe2x80x94 is 
wherein
RA is isopropyl or tert-butyl,
RB is isopropyl or tert-butyl,
RC is isopropyl, tert-butyl, phenyl, thiophen-2-yl, 2-methylpropenyl or 3-butenyl,
xe2x80x83and a pharmaceutically acceptable salt thereof;
[7] the heterocyclic compound of the above-mentioned [1] wherein, in the formula [I],
Yxe2x80x94Axe2x80x94 is 
xe2x80x83and a pharmaceutically acceptable salt thereof;
[8] the heterocyclic compound of the above-mentioned [1] wherein, in the formula [I],
Yxe2x80x94Axe2x80x94 is 
and a pharmaceutically acceptable salt thereof;
[9] the heterocyclic compound of the above-mentioned [1] wherein the heterocyclic compound of the formula [I] is any of the following compounds (1) to (67):
(1) 7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(2) 2-benzyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(3) 2-acetyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(4) 2-methyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(5) 2-hexanoyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(6) 2-hexyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(7) 2-isobutyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(8) 2-cyclohexylmethyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(9) 7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-2-(3-phenylpropyl)-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(10) 2-benzoyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(11) 2-benzyl-7-[2-(N-methyl-N-(pyridin-2-yl)amino)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(12) 2-benzyl-7-[2-(5-ethyl-pyridin-2-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(13) 2-benzyl-7-[2-(indolin-1-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(14) ethyl 2-benzyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate,
(15) methyl 7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate,
(16) 2-(4-methoxybenzyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(17) ethyl 2-(4-methoxybenzyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate,
(18) 2-(4-methylbenzyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(19) ethyl 2-(4-methylbenzyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate,
(20) 2-benzyl-7-[2-(6-carboxyindolin-1-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(21) 2-(4-fluorobenzyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(22) 2-(2,2-dimethylpropionyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(23) 2-(2,2-dimethylpropyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(24) 2-benzyl-7-[2-(5-methyl-2-tert-butyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(25) 2-benzyl-7-[2-(5-methyl-2-(thiophen-2-yl)oxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(26) 2-benzyl-7-[2-(5-methyl-2-isopropyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(27) 2-butyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(28) 2-benzyl-7-{2-[5-methyl-2-(2-methylpropenyl)oxazol-4-yl]ethoxy}-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(29) 2-benzyl-7-{2-[2-(3-butenyl)-5-methyloxazol-4-yl]ethoxy}-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(30) 2-allyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(31) 7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-2-(2-propynyl)-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(32) 2-(2-butenyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(33) 2-benzyl-7-[(indolin-3-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(34) 2-(3-butenyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(35) 7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-2-pentanoyl-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(36) 7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-2-(4-pentenoyl)-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(37) 2-(3-methyl-2-butenoyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(38) 2-(3,3-dimethylbutyryl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(39) 2-benzyl-7-methoxy-6-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3RS)-carboxylic acid,
(40) 7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-2-(pyridin-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(41) 2-benzyl-7-(3-methyl-3-phenylbutoxy)-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(42) 2-benzyl-7-(3,3-dimethyl-4-phenylbutoxy)-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(43) 2-benzyl-7-(2-isopropylbenzoxazol-6-yl)methoxy-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(44) 2-benzyl-7-(2-tert-butylbenzoxazol-6-yl)methoxy-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(45) 2-benzyl-7-(2-tert-butylbenzoxazol-5-yl)methoxy-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(46) 7-(2-tert-butylbenzoxazol-6-yl)methoxy-2-(2,2-dimethylpropyl)-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(47) 2-benzyl-7-(2-isopropylbenzoxazol-5-yl)methoxy-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(48) 7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-2-(pyridin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(49) 7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-2-[(pyridin-2-yl)carbonyl]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(50) methyl 2-benzyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate,
(51) 2-benzyl-7-[2-(2-cyclopropyl-5-methyloxazol-4-yl)-ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(52) 2-(3-methyl-2-butenyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(53) 2-(2,2-dimethylpropyl)-7-[2-(5-methyl-2-tert-butyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(54) 2-benzyl-7-{2-[2-(1-butenyl)-5-methyloxazol-4-yl]ethoxy}-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(55) 2-benzyl-7-{2-[2-(2,2-dimethylpropyl)-5-methyloxazol-4-yl]ethoxy}-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(56) ethyl 2-(2,2-dimethylpropyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate,
(57) 7-(benzofran-2-ylmethoxy)-2-benzyl-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(58) 2-isobutyryl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(59) 7-[2-(benzofran-2-yl)ethoxy]-2-benzyl-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(60) 7-[2-(5-ethylpyridin-2-yl)ethoxy]-2-hexanoyl-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(61) 2-carboxymethyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(62) 2-[3-(methoxycarbonyl)propionyl]-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(63) 2-[3-(ethoxycarbonyl)propyl]-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(64) 2-benzyl-6-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3RS)-carboxylic acid,
(65) 2-(3-acetylbenzyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(66) 2-(2-acetylbenzyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid, and
(67) 2-benzyl-7-[(5-methyl-2-phenyloxazol-4-yl)methoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid, and a pharmaceutically acceptable salt thereof;
[10] the heterocyclic compound of the above-mentioned [9] wherein the heterocyclic compound of the formula [I] is any of the above-mentioned compounds (1) to (47), and a pharmaceutically acceptable salt thereof;
[11] the heterocyclic compound of the above-mentioned [9] wherein the heterocyclic compound of the formula [I] is any of the above-mentioned compounds (1) to (21), and a pharmaceutically acceptable salt thereof;
[12] a pharmaceutical composition comprising the heterocyclic compound of any of the above-mentioned [1] to [11] or a pharmaceutically acceptable salt thereof;
[13] a pharmaceutical agent comprising the heterocyclic compound of any of the above-mentioned [1] to [11] or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of a hypoglycemic agent, a hypolipidemic agent, an insulin resistance improver, a therapeutic agent of diabetes, a therapeutic agent of diabetic complication, a glucose tolerance improver, an anti-atherosclerosis agent, an anti-obesity agent, an antiinflammatory agent, an agent for the prophylaxis or treatment of PPAR-mediated disease and an agent for the prophylaxis or treatment of syndrome X;
[14] a hypoglycemic agent comprising the heterocyclic compound of any of the above-mentioned [1] to [11] or a pharmaceutically acceptable salt thereof;
[15] a hypolipidemic agent comprising the heterocyclic compound of any of the above-mentioned [1] to [11] or a pharmaceutically acceptable salt thereof;
[16] an insulin resistance improver comprising the heterocyclic compound of any of the above-mentioned [1] to [11] or a pharmaceutically acceptable salt thereof;
[17] a therapeutic agent of diabetic complications, comprising the heterocyclic compound of any of the above-mentioned [1] to [11] or a pharmaceutically acceptable salt thereof; and
[18] a therapeutic agent of diabetes, comprising the heterocyclic compound of any of the above-mentioned [1] to [11] or a pharmaceutically acceptable salt thereof.
The novel heterocyclic compound of the formula [I] 
wherein
R1 is hydrogen atom or lower alkyl,
R2 is hydrogen atom, alkyl optionally having a substituent, cycloalkyl, cycloalkylalkyl, aryl optionally having a substituent, arylalkyl optionally having a substituent, alkenyl optionally having a substituent, alkynyl optionally having a substituent, heterocyclic alkyl optionally having a substituent or xe2x80x94COR4 
wherein R4 is hydrogen atom, alkyl optionally having a substituent, aryl optionally having a substituent, alkenyl optionally having a substituent, arylalkyl optionally having a substituent or heterocyclic residue optionally having a substituent,
R3 is hydrogen atom, lower alkyl or lower alkoxy,
A is a single bond or  greater than Nxe2x80x94R5 wherein R5 is hydrogen atom or lower alkyl,
B is lower alkylene, and
Y is aryl optionally having a substituent or an aromatic heterocyclic residue optionally having a substituent
and a pharmaceutically acceptable salt thereof have a hypoglycemic action, a blood hypolipidemic action, an insulin resistance-improving action and a PPAR-activating action.
The alkoxycarbonyl in the present invention preferably has 2 to 5 carbon atoms. Examples thereof include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl and the like.
The lower alkyl at R1, R3 and R5 is preferably straight chain or branched chain alkyl having 1 to 6 carbon atoms, which is exemplified by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl and the like, preferably methyl, ethyl, propyl and isopropyl.
The lower alkoxy at R3 is preferably straight chain or branched chain alkoxy having 1 to 6 carbon atoms, which is exemplified by methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy and the like, preferably methoxy, ethoxy, propoxy and isopropoxy.
The xe2x80x9calkenylxe2x80x9d, in the alkenyl optionally having a substituent at R2 and R4 is preferably straight chain or branched chain alkenyl having 2 to 6 carbon atoms, which is exemplified by vinyl, 1-propenyl, 2-propenyl, isopropenyl, allyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl and the like, preferably allyl, 2-butenyl, 3-butenyl, 4-pentenyl, 2-propenyl and 2-methyl-1-propenyl. As the substituent, exemplified are lower alkoxy (as defined for lower alkoxy at R3), hydroxy, carboxy, alkoxycarbonyl, halogen atom (chlorine atom, bromine atom, iodine atom and fluorine atom), nitro, amino and the like. When alkenyl at R2 or R4 is substituted, the number of the substituent is preferably 1 or 2.
The xe2x80x9calkynylxe2x80x9d in the alkynyl optionally having a substituent at R2 is preferably straight chain or branched chain alkynyl having 2 to 4 carbon atoms, which is exemplified by ethynyl, 1-propynyl, 2-propynyl, 1-methyl-2-propynyl and the like, preferably ethynyl and 2-propynyl. As the substituent, exemplified are lower alkoxy (as defined for lower alkoxy at R3), hydroxy, carboxy, alkoxycarbonyl, halogen atom (chlorine atom, bromine atom, iodine atom and fluorine atom), nitro, amino and the like. When alkynyl at R2 is substituted, the number of the substituent is preferably 1 or 2.
The xe2x80x9calkylxe2x80x9d in the alkyl optionally having a substituent at R2 and R4 is preferably straight chain or branched chain alkyl having 1 to 8 carbon atoms, which is exemplified by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl and the like, preferably methyl, ethyl, isobutyl, propyl, hexyl, pentyl and isopropyl. As the substituent, exemplified are lower alkoxy (as defined for lower alkoxy at R3), hydroxy, carboxy, alkoxycarbonyl, halogen atom (chlorine atom, bromine atom, iodine atom and fluorine atom), nitro, amino and the like. When alkyl at R2 is substituted, the number of the substituent is preferably 1 or 2.
The cycloalkyl at R2 is preferably cycloalkyl having 3 to 8 carbon atoms, which is exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like, preferably cyclopropyl, cyclopentyl and cyclohexyl.
The cycloalkylalkyl at R2 is that wherein cycloalkyl moiety is preferably cycloalkyl having 3 to 8 carbon atoms and alkyl moiety is preferably straight chain or branched chain alkyl having 1 to 3 carbon atoms. Examples thereof are cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, 2-cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl, 2-cyclohexylethyl, 2-cycloheptylethyl, 2-cyclooctylethyl, 3-cyclopropylpropyl, 3-cyclobutylpropyl, 3-cyclopentylpropyl, 3-cyclohexylpropyl, 3-cycloheptylpropyl, 3-cyclooctylpropyl, 1-cyclohexylethyl, 1-cyclohexylpropyl, 2-cyclohexylpropyl and the like, preferably cyclohexylmethyl, 2-cyclohexylethyl, cyclopentylmethyl and 2-cyclopentylethyl.
The aryl in the aryl optionally having a substituent at R2, R4 and Y is exemplified by phenyl, naphthyl and the like. As the substituent, exemplified are lower alkyl (as defined for lower alkyl at R1, R3 and R5), lower alkoxy (as defined for lower alkoxy at R3), hydroxy, carboxy, alkoxycarbonyl, halogen atom (chlorine atom, bromine atom, iodine atom and fluorine atom), nitro, amino, acyl (e.g., formyl, acetyl, propanoyl etc.) and the like. When aryl at Y is substituted, the number of the substituent is preferably 1 or 2.
The arylalkyl optionally having a substituent at R2 and R4 is exemplified by that wherein aryl moiety is preferably phenyl, naphthyl and the like, and alkyl moiety is preferably straight chain or branched chain alkyl having 1 to 3 carbon atoms. Examples of arylalkyl are benzyl, 1-naphthylmethyl, 2-naphthylmethyl, 2-phenylethyl, 2-(1-naphthyl)ethyl, 2-(2-naphthyl)ethyl, 3-phenylpropyl, 3-(1-naphthyl)propyl, 3-(2-naphthyl)propyl, 1-phenylethyl, 2-phenylpropyl, 1-(1-naphthyl)ethyl, 1-(2-naphthyl)ethyl, 1-(1-naphthyl)propyl, 1-(2-naphthyl)propyl, 2-(1-naphthyl)propyl, 2-(2-naphthyl)propyl and the like, preferably benzyl, 3-phenylpropyl, 1-naphthylmethyl and 2-naphthylmethyl. As the substituent, exemplified are lower alkyl (as defined for lower alkyl at R1, R3 and R5), lower alkoxy (as defined for lower alkoxy at R3), hydroxy, carboxy, alkoxycarbonyl, halogen atom (chlorine atom, bromine atom, iodine atom and fluorine atom), nitro, amino, acyl (e.g., formyl, acetyl, propanoyl etc.) and the like, preferably lower alkyl, lower alkoxy, halogen atom and acyl. When arylalkyl at Y is substituted, the number of the substituent is preferably 1 or 2.
The aromatic heterocycle in the aromatic heterocyclic residue optionally having a substituent at Y is preferably a monocyclic heterocycle or a condensed heterocycle containing at least one hetero atom selected from the group consisting of oxygen atom, nitrogen atom and sulfur atom. The condensed heterocycle in the present invention has two rings and encompasses that having hetero atom(s) on the both rings. Preferable monocyclic heterocycle includes a 5- or 6-membered ring. The heterocycle constituting the condensed heterocycle is preferably a 5- or 6-membered ring. The ring without a hetero atom, which constitutes the condensed heterocycle, is preferably a 5- or 6-membered ring. Examples of the aromatic heterocyclic residue are monocyclic heterocyclic residue such as furyl, thienyl, pyridyl, imidazolyl, pyrazolyl, oxazolyl, isooxazolyl, thiazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridazinyl, pyrimidinyl or pyrazinyl and the like; a condensed heterocyclic residue such as indolyl, isoindolyl, indolinyl, isoindolinyl, indazolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolyl, isoquinolyl, benzoxazinyl, benzothiazinyl, furo[2,3-b]pyridyl, thieno[2,3-b]pyridyl, naphthyridinyl, imidazopyridyl, oxazolopyridyl, thiazolopyridyl and the like, with preference given to pyridyl, oxazolyl, indolinyl, benzoxazolyl, thiazolyl, benzothiazolyl, indolyl, quinolyl and benzofuranyl. As the substituent, exemplified are lower alkyl (as defined for lower alkyl at R1, R3 and R5), lower alkoxy (as defined for lower alkoxy at R3), hydroxy, carboxy, alkoxycarbonyl, halogen atom (chlorine atom, bromine atom, iodine atom and fluorine atom), nitro, amino aryl (e.g., phenyl, naphthyl and the like), heterocyclic residue (e.g., thienyl, pyridyl, furyl and the like), alkenyl (as defined for alkenyl at R2 and R4), cycloalkyl (e.g., cyclopropyl etc.) and the like, preferably aryl, lower alkyl, carboxy, heterocyclic residue, alkenyl and cycloalkyl. When aromatic heterocyclic residue at Y is substituted, the number of the substituent is preferably 1 or 2.
The lower alkylene at B is preferably straight chain or branched chain alkylene having 1 to 6 carbon atoms, which is exemplified by methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, methylmethylene, 2,2-dimethyltrimethylene, 2-ethyltrimethylene, 1-methyltetramethylene, 2-methyltetramethylene, 3-methyltetramethylene, 3,3-dimethyltrimethylene, 3,3-dimethyltetramethylene and the like, preferably ethylene, trimethylene and tetramethylene.
The heterocyclic moiety in the heterocyclic alkyl optionally having a substituent at R2 is as defined for the xe2x80x9caromatic heterocyclic residuexe2x80x9d in the xe2x80x9caromatic heterocyclic residue optionally having a substituentxe2x80x9d at Y. As the alkyl moiety, exemplified is straight chain or branched chain alkyl having 1 to 3 carbon atoms. The specific examples of the heterocyclic alkyl are 1-pyridylmethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl; 1-(1-pyridyl)ethyl, 1-(2-pyridyl)ethyl, 1-(3-pyridyl)ethyl, 1-(4-pyridyl)ethyl, 2-(1-pyridyl)ethyl, 2-(2-pyridyl)ethyl, 2-(3-pyridyl)ethyl, 2-(4-pyridyl)ethyl; 1-(1-pyridyl)propyl, 1-(2-pyridyl)propyl, 1-(3-pyridyl)propyl, 1-(4-pyridyl)propyl, 2-(1-pyridyl)propyl, 2-(2-pyridyl)propyl, 2-(3-pyridyl)propyl, 2-(4-pyridyl)propyl, 3-(1-pyridyl)propyl, 3-(2-pyridyl)propyl, 3-(3-pyridyl)propyl, 3-(4-pyridyl)propyl; 2-thienylmethyl, 3-thienylmethyl; 1-(2-thienyl)ethyl, 1-(3-thienyl)ethyl, 2-(2-thienyl)ethyl, 2-(3-thienyl)ethyl; 1-(2-thienyl)propyl, 1-(3-thienyl)propyl, 2-(2-thienyl)propyl, 2-(3-thienyl)propyl, 3-(2-thienyl)propyl, 3-(3-thienyl)propyl; and the like. The heterocyclic alkyl may be substituted at the heterocyclic moiety. As the substituent, exemplified are lower alkyl (as defined for lower alkyl at R1, R3 and R5), lower alkoxy (as defined for lower alkoxy at R3), hydroxy, carboxy, alkoxycarbonyl, halogen atom (chlorine atom, bromine atom, iodine atom and fluorine atom), nitro, amino and the like. When the heterocyclic moiety is substituted, the number of the substituent is preferably 1 or 2.
With regard to the heterocyclic residue optionally having a substituent at R4, the heterocyclic moiety is the same as the xe2x80x9caromatic heterocyclic residuexe2x80x9d in the xe2x80x9caromatic heterocyclic residue optionally having a substituentxe2x80x9d at Y, which is preferably pyridyl. The heterocyclic residue may be substituted. As the substituent, exemplified are lower alkyl (as defined for lower alkyl at R1, R3 and R5), lower alkoxy (as defined for lower alkoxy at R3), hydroxy, carboxy, alkoxycarbonyl, halogen atom (chlorine atom, bromine atom, iodine atom and fluorine atom), nitro, amino and the like. When the heterocyclic moiety is substituted, the number of the substituent is preferably 1 or 2.
The heterocyclic compound [I] and a pharmaceutically acceptable salt thereof are preferably exemplified by the following.
A heterocyclic compound of the above-mentioned formula [I], wherein
(1) R1 is hydrogen atom or lower alkyl,
R2 is hydrogen atom, alkyl optionally having a substituent, cycloalkyl, cycloalkylalkyl, aryl optionally having a substituent, arylalkyl optionally having a substituent or xe2x80x94COR4 wherein R4 is hydrogen atom, alkyl optionally having a substituent, aryl optionally having a substituent or arylalkyl optionally having a substituent,
R3 is hydrogen atom, lower alkyl or lower alkoxy,
A is a single bond or  greater than Nxe2x80x94R5 wherein R5 is hydrogen atom or lower alkyl,
B is lower alkylene, and
Y is aryl optionally having a substituent or an aromatic heterocyclic residue optionally having a substituent,
(2) R1 is hydrogen atom or lower alkyl,
R2 is hydrogen atom, alkyl, cycloalkylalkyl, arylalkyl optionally having a substituent, alkenyl, alkynyl, heterocyclic alkyl or xe2x80x94COR4 wherein R4 is alkyl, alkenyl or aryl,
R3 is hydrogen atom or lower alkoxy,
A is a single bond or  greater than Nxe2x80x94R5 wherein R5 is lower alkyl,
B is lower alkylene, and
Y is aryl or an aromatic heterocyclic residue optionally having a substituent, or
(3) R1 is hydrogen atom or lower alkyl,
R2 is hydrogen atom, alkyl, cycloalkylalkyl, arylalkyl optionally having a substituent or xe2x80x94COR4 wherein R4 is alkyl or aryl,
R3 is hydrogen atom,
A is a single bond or  greater than Nxe2x80x94R5 wherein R5 is lower alkyl,
B is lower alkylene, and
Y is an aromatic heterocyclic residue optionally having a substituent and a pharmaceutically acceptable salt thereof.
In the formula [I], Yxe2x80x94Axe2x80x94 is preferably 
wherein
RA is isopropyl or tert-butyl,
RB is isopropyl or tert-butyl, and
RC is isopropyl, tert-butyl, phenyl, thiophen-2-yl, 2-methylpropenyl or 3-butenyl; or 
wherein
RA is isopropyl or tert-butyl,
RB is isopropyl or tert-butyl,
RC is isopropyl, tert-butyl, phenyl, thiophen-2-yl, 2-methylpropenyl, 3-butenyl, cyclopropyl, 1-butenyl or 2,2-dimethylpropyl, with particular preference given to 
Preferable examples of the heterocyclic compound [I] and the pharmaceutically acceptable salt thereof are
(1) 7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(2) 2-benzyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(3) 2-acetyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(4) 2-methyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(5) 2-hexanoyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(6) 2-hexyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(7) 2-isobutyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(8) 2-cyclohexylmethyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(9) 7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-2-(3-phenylpropyl)-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(10) 2-benzoyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(11) 2-benzyl-7-[2-(N-methyl-N-(pyridin-2-yl)amino)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(12) 2-benzyl-7-[2-(5-ethyl-pyridin-2-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(13) 2-benzyl-7-[2-(indolin-1-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(14) ethyl 2-benzyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate,
(15) methyl 7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate,
(16) 2-(4-methoxybenzyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(17) ethyl 2-(4-methoxybenzyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate,
(18) 2-(4-methylbenzyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(19) ethyl 2-(4-methylbenzyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate,
(20) 2-benzyl-7-[2-(6-carboxyindolin-1-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid, and
(21) 2-(4-fluorobenzyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid, and pharmaceutically acceptable salt thereof. Besides the above-mentioned, preferred are
(22) 2-(2,2-dimethylpropionyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(23) 2-(2,2-dimethylpropyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(24) 2-benzyl-7-[2-(5-methyl-2-tert-butyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(25) 2-benzyl-7-[2-(5-methyl-2-(thiophen-2-yl)oxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(26) 2-benzyl-7-[2-(5-methyl-2-isopropyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(27) 2-butyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(28) 2-benzyl-7-{2-[5-methyl-2-(2-methylpropenyl)oxazol-4-yl]ethoxy}-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(29) 2-benzyl-7-{2-[2-(3-butenyl)-5-methyloxazol-4-yl]-ethoxy}-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(30) 2-allyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(31) 7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-2-(2-propynyl)-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(32) 2-(2-butenyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(33) 2-benzyl-7-[(indolin-3-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(34) 2-(3-butenyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(35) 7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-2-pentanoyl-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(36) 7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-2-(4-pentenoyl)-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(37) 2-(3-methyl-2-butenoyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(38) 2-(3,3-dimethylbutyryl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(39) 2-benzyl-7-methoxy-6-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3RS)-carboxylic acid,
(40) 7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-2-(pyridin-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(41) 2-benzyl-7-(3-methyl-3-phenylbutoxy)-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(42) 2-benzyl-7-(3,3-dimethyl-4-phenylbutoxy)-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(43) 2-benzyl-7-(2-isopropylbenzoxazol-6-yl)methoxy-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(44) 2-benzyl-7-(2-tert-butylbenzoxazol-6-yl)methoxy-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(45) 2-benzyl-7-(2-tert-butylbenzoxazol-5-yl)methoxy-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(46) 7-(2-tert-butylbenzoxazol-6-yl)methoxy-2-(2,2-dimethylpropyl)-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid, and
(47) 2-benzyl-7-(2-isopropylbenzoxazol-5-yl)methoxy-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid, and pharmaceutically acceptable salts thereof.
In addition to the above-mentioned, the following heterocyclic compound [I] and pharmaceutically acceptable salts thereof are preferable.
(48) 7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-2-(pyridin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(49) 7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-2-[(pyridin-2-yl)carbonyl]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(50) methyl 2-benzyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate,
(51) 2-benzyl-7-[2-(2-cyclopropyl-5-methyloxazol-4-yl)-ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(52) 2-(3-methyl-2-butenyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(53) 2-(2,2-dimethylpropyl)-7-[2-(5-methyl-2-tert-butyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(54) 2-benzyl-7-{2-[2-(1-butenyl)-5-methyloxazol-4-yl]ethoxy}-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(55) 2-benzyl-7-{2-[2-(2,2-dimethylpropyl)-5-methyloxazol-4-yl]ethoxy}-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(56) ethyl 2-(2,2-dimethylpropyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate,
(57) 7-(benzofran-2-ylmethoxy)-2-benzyl-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(58) 2-isobutyryl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(59) 7-[2-(benzofran-2-yl)ethoxy]-2-benzyl-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(60) 7-[2-(5-ethylpyridin-2-yl)ethoxy]-2-hexanoyl-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(61) 2-carboxymethyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(62) 2-[3-(methoxycarbonyl)propionyl]-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(63) 2-[3-(ethoxycarbonyl)propyl]-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(64) 2-benzyl-6-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3RS)-carboxylic acid,
(65) 2-(3-acetylbenzyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(66) 2-(2-acetylbenzyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,
(67) 2-benzyl-7-[(5-methyl-2-phenyloxazol-4-yl)methoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid.
Since the heterocyclic compound [I] has an asymmetric carbon at the 3-position of the 1,2,3,4-tetrahydroisoquinoline ring, it includes various stereoisomers. The most preferable configuration is 
wherein R1, R2, R3, Y, A and B are as defined above.
The heterocyclic compound [I] can be converted to a pharmaceutically acceptable salt as necessary.
When the heterocyclic compound [I] has a basic group, an acid addition salt can be formed. The acid used for forming the acid addition salt is not subject to any particular limitation as long as it can form a salt with a basic moiety and it is a pharmaceutically acceptable acid. Examples of the acid include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid and the like, and organic acids such as oxalic acid, fumaric acid, maleic acid, citric acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid and the like, and the like.
When the heterocyclic compound [I] has an acidic group (e.g., carboxyl group and the like), a salt such as an alkali metal salt (e.g., sodium salt, potassium salt and the like), an alkaline earth metal salt (e.g., calcium salt, magnesium salt and the like) or an organic base salt (e.g., triethylamine salt, dicyclohexylamine salt, pyridine salt and the like) and the like may be formed.
The heterocyclic compound [I] and the pharmaceutically acceptable salt thereof can be produced according to any of the following Production Methods. 
wherein R1, R3, A, B and Y are as defined above, R6 is hydrogen atom, alkyl optionally having a substituent, cycloalkyl, cycloalkylalkyl, aryl optionally having a substituent, arylalkyl optionally having a substituent, alkenyl optionally having a substituent, alkynyl optionally having a substituent, heterocyclic alkyl optionally having a substituent, xe2x80x94COR4 (R4 is as defined above) or amino-protecting group, and X is hydroxy, halogen atom (fluorine atom, chlorine atom, bromine atom or iodine atom), or a leaving group such as alkanesulfonyloxy (e.g., methanesulfonyloxy, ethanesulfonyloxy, propanesulfonyloxy, trifluoromethanesulfonyloxy and the like), arylsulfonyloxy (e.g., phenylsulfonyloxy, tolylsulfonyloxy and the like) and the like.
In Production Method 1, the compound of formula [Ia] (also referred to as compound [Ia]) is synthesized by the reaction of the compound of the formula [II] (also referred to as compound [II]) with the compound of the formula [III] (also referred to as compound [III]).
The xe2x80x9calkyl optionally having a substituentxe2x80x9d, xe2x80x9ccycloalkylxe2x80x9d, xe2x80x9ccycloalkylalkylxe2x80x9d, xe2x80x9caryl optionally having a substituentxe2x80x9d, xe2x80x9carylalkyl optionally having a substituentxe2x80x9d, xe2x80x9calkenyl optionally having a substituentxe2x80x9d, xe2x80x9calkynyl optionally having a substituentxe2x80x9d and xe2x80x9cheterocyclic alkyl optionally having a substituentxe2x80x9d at R6 are as defined for R2.
Examples of the amino-protecting group at R6 are formyl, monochloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, diphenylmethyloxycarbonyl, methoxymethylcarbonyl, methoxymethyloxycarbonyl, trimethylsilyl, 2,2,2-trichloroethoxycarbonyl, 2-methylsulfonylethyloxycarbonyl, tert-butoxycarbonyl (hereinafter to be referred to as Boc), trityl and the like.
Production Method 1-a: When X is hydroxy, Production Method 1 comprises a dehydrating reaction such as Mitsunobu Reaction (Reagents for Organic Synthesis, Fisher and Fisher, Vol. 6, 645) and the like. The reaction is generally carried out in a solvent with an azo compound and phosphine. As the azo compound, exemplified are di(C1-C4 alkyl) azodicarboxylate (e.g., diethyl azodicarboxylate and the like), azodicarboxamide (e.g., 1,1xe2x80x2-(azodicarbonyl)dipiperidine and the like) and the like. As the phosphine, exemplidfied are triarylphosphine (e.g., triphenylphosphine and the like), tri(C1-C4alkyl)phosphine (e.g., tributylphosphine and the like), and the like.
As the solvent used in the Production Method 1-a, exemplified are dioxane, acetonitrile, tetrahydrofuran, chloroform, methylene chloride, ethylene chloride, benzene, toluene, xylene, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide and the like; and a mixture thereof and the like, but the solvent is not limited as far as it does not adversely influence the reaction.
The amount of the compound [II] used in the Production Method 1-a is not subject to any particular limitation. It is used in an amount of generally 1-5 mol, preferably 1-3 mol, per 1 mol of compound [III]. The azo compound and phosphine are respectively used in an amount of generally 1-3 mol, preferably 1-1.5 mol, per 1 mol of compound [III].
While the reaction conditions such as reaction temperature and reaction time and the like in Production Method 1-a vary depending on the reagent, solvent and the like to be used in this reaction, the reaction generally proceeds at a temperature of from xe2x88x9230xc2x0 C. to 50xc2x0 C. for 30 min to about a dozen hours.
Production Method 1-b: When X is halogen atom or leaving group such as alkanesulfonyloxy (e.g., methanesulfonyloxy, ethanesulfonyloxy, propanesulfonyloxy, trifluoromethanesulfonyloxy and the like), arylsulfonyloxy (e.g., phenylsulfonyloxy, tolylsulfonyloxy and the like) and the like, Production Method 1-b is performed in a solvent similar to that used in the Production Method 1-a and in the presence of a base.
The base used in the Production Method 1-b is exemplified by, but not particulary limited to, inorganic base such as alkali metal carbonate (e.g., sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate and the like), alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide and the like), metal hydride compound (e.g., sodium hydride, potassium hydride, calcium hydride and the like) and the like; organic base such as alkali metal alkoxide (e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like), amines (e.g., triethylamine, diisopropylethylamine and the like) and the like.
The amount of the compound [II] used in the Production Method 1-b is not subject to any particular limitation. It is used in an amount of generally 1-5 mol, preferably 1-3 mol, per 1 mol of compound [III]. The base is used in an amount of generally 1-5 mol, preferably 1-3 mol, per 1 mol of compound [III].
While the reaction conditions such as reaction temperature and reaction time and the like in Production Method 1-b vary depending on the reagent, solvent and the like to be used in this reaction, the reaction generally proceeds at a temperature of from xe2x88x9230xc2x0 C. to 150xc2x0 C. for 30 min to about a dozen hours.
In the Production Method 1, R1 of compound [III] is preferably lower alkyl. In this case, compound [Ia] wherein R1 is lower alkyl is obtained, and this compound may be led to the compound [Ia] wherein R1 is hydrogen atom, by hydrolysis according to a method known per se.
In the Production Method 1, when R6 of compound [III] is amino-protecting group, compound [Ia] wherein R6 is amino-protecting group is obtained. This compound may be led to the compound [Ia] wherein R6 is hydrogen atom, by deprotection according to a method known per se. 
wherein R1, R3, A, B and Y are as defined above, R7 is amino-protecting group, R8 is alkyl optionally having a substituent, cycloalkyl, cycloalkylalkyl, aryl optionally having a substituent, arylalkyl optionally having a substituent, alkenyl optionally having a substituent, alkynyl optionally having a substituent or heterocyclic alkyl optionally having a substituent, and U is halogen atom (fluorine atom, chlorine atom, bromine atom, iodine atom), or a leaving group such as alkanesulfonyloxy (e.g., methanesulfonyloxy, ethanesulfonyloxy, propanesulfonyloxy, trifluoromethanesulfonyloxy and the like), arylsulfonyloxy (e.g., phenylsulfonyloxy, tolylsulfonyloxy and the like) and the like.
In Production Method 2, the amino-protecting group R7 of a compound of the formula [Ib] (also referred to as compound [Ib]) is eliminated by a method known per se to give a compound of the formula [Ic] (also referred to as compound [Ic]), which is then reacted with a compound of the formula [V] (also referred to as compound [V]), whereby a compound of the formula [Id] (also referred to as compound [Id]) is produced.
The xe2x80x9calkyl optionally having a substituentxe2x80x9d, xe2x80x9ccycloalkylxe2x80x9d, xe2x80x9ccycloalkylalkylxe2x80x9d, xe2x80x9caryl optionally having a substituentxe2x80x9d, xe2x80x9carylalkyl optionally having a substituentxe2x80x9d, xe2x80x9calkenyl optionally having a substituentxe2x80x9d, xe2x80x9calkynyl optionally having a substituentxe2x80x9d and xe2x80x9cheterocyclic alkyl optionally having a substituentxe2x80x9d at R8 are as defined for R2.
The amino-protecting group at R7 is as defined for R6.
In the Production Method 2, compound [Ic] is reacted with compound [V] in a solvent that does not inhibit the reaction, such as dioxane, acetonitrile, tetrahydrofuran, chloroform, methylene chloride, ethylene chloride, benzene, toluene, xylene, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide and the like; and a mixture thereof and the like, in the presence of a base, to give compound [Id].
In the Production Method 2, the base used for the reaction of compound [Ic] with compound [V] is exemplified, but not particulary limited to, inorganic base such as alkali metal carbonate (e.g., sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate and the like), alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide and the like), metal hydride compound (e.g., sodium hydride, potassium hydride and calcium hydride and the like) and the like; and organic base such as alkali metal alkoxide (e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like), amines (e.g., triethylamine, diisopropylethylamine and the like) and the like.
The amount of the compound [V] used in the Production Method 2 is generally 1-5 mol, preferably 1-3 mol, per 1 mol of compound [Ic]. The base is used in an amount of generally 1-5 mol, preferably 1-3 mol, per 1 mol of compound [Ic].
While the reaction conditions such as reaction temperature and reaction time and the like for the reaction of compound [Ic] with compound [V] in the Production Method 2 vary depending on the reagent, solvent and the like to be used in this reaction, the reaction generally proceeds at a temperature of from xe2x88x9230xc2x0 C. to 150xc2x0 C. for 30 min to about two dozen hours.
In the Production Method 2, R1 of compound [Ib] is preferably lower alkyl. In this case, compound [Id] wherein R1 is lower alkyl is obtained, and this compound may be led to the compound [Id] wherein R1 is hydrogen atom, by hydrolysis according to a method known per se. 
wherein R1, R3, R4, A, B and Y are as defined above.
In Production Method 3, a compound of the formula [Ie] (also referred to as compound [Ie]) is synthesized by reacting compound [Ic] with a compound of the formula [VI] (also referred to as compound [VI]).
In the Production Method 3, compound [VI] may be used not only in the form of a free acid, but also in the form of a salt (e.g., sodium salt, potassium salt, calcium salt, triethylamine salt, pyridine salt and the like) or as a reactive derivative (e.g., acid halide such as acid chloride, acid bromide and the like; acid anhydride; mixed acid anhydride with substituted phosphoric acid such as dialkyl phosphate and the like, and alkyl carbonate such as monoethyl carbonate and the like; reactive amide which is amide with imidazole and the like; ester such as cyanomethyl ester and 4-nitrophenyl ester and the like), and the like.
In the Production Method 3, when the compound [VI] is used in the form of a free acid or a salt, this reaction is preferably carried out in the presence of a condensing agent. As the condensing agent, a dehydrating agent such as carbodiimide compound (e.g., N,Nxe2x80x2-dicyclohexylcarbodiimide, 1-ethyl-3-(3xe2x80x2-dimethylaminopropyl)carbodiimide, N-cyclohexyl-Nxe2x80x2-morpholinoethylcarbodiimide, N-cyclohexyl-Nxe2x80x2-(4-diethylaminocyclohexyl)carbodiimide and the like), azolide compound (e.g., N,Nxe2x80x2-carbonyldiimidazole, N,Nxe2x80x2-thionyldiimidazole and the like) and the like, and the like can be used. The condensing agent is used in an amount of generally 1-5 mol, preferably 1-3 mol, per 1 mol of compound [Ic]. It is considered that, when a condensing agent is used, compound [VI] becomes a reactive derivative and proceeds to the reaction.
The Production Method 3 is generally performed in a solvent inert to the reaction. As the solvent, exemplified are acetone, dioxane, acetonitrile, chloroform, benzene, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine, water and a mixed solvent thereof. In the Production Method 3, a base such as triethylamine, pyridine, 4-dimethylaminopyridine, potassium carbonate and the like can be used. When the base is used, it is used in an amount of generally 1-5 mol, preferably 1-3 mol, per 1 mol of compound [Ic].
In Production Method 3, compound [VI] is used in an amount of generally 1-5 mol, preferably 1-3 mol, per 1 mol of compound [Ic].
While the reaction conditions such as reaction temperature and reaction time and the like in the reaction of compound [VI] with compound [Ic] in the Production Method 3 vary depending on the reagent, solvent and the like to be used in this reaction, the reaction generally proceeds at a temperature of from xe2x88x9230xc2x0 C. to 150xc2x0 C. for 10 min to about a dozen hours.
In the Production Method 3, compound [Iexe2x80x2] is obtained by reacting compound [VI] with compound [Ic], isolating and reducing the resulting compound [Ie]. This reduction reaction is carried out in a solvent that does not adversely influence the reaction (e.g., water, methanol, ethanol, dioxane, acetonitrile, tetrahydrofuran, chloroform, methylene chloride, ethylene chloride, benzene, toluene, xylene, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, a mixture thereof and the like) in the presence of a reducing agent.
The reducing agent used in this reduction is exemplified by metal hydride complex (e.g., lithium aluminum hydride, sodium cyanoborohydride (NaBH3CN), sodium borohydride and the like), borane and the like. The agent is not subject to any particular limitation as long as it is generally used for reducing a carbonyl group to a methylene group. The reducing agent is used in an amount of generally 1-5 mol, preferably 1-3 mol, per 1 mol of compound [Ie].
While the reaction conditions such as reaction temperature and reaction time and the like in the reduction reaction vary depending on the reagent, solvent and the like to be used in this reaction, the reaction generally proceeds at a temperature of from xe2x88x9230xc2x0 C. to 150xc2x0 C. for 30 min to about a dozen hours. 
wherein R1, R2, R3, R5, B, X, Y and U are as defined above, and R10 is an amino-protecting group.
The amino-protecting group at R10 is as defined for R6.
Production Method 4 is intended for the heterocyclic compound [I] wherein A is  greater than Nxe2x80x94R5. In this method, compound of the formula [VII] (also referred to as compound [VII]) is reacted with compound of the formula [VIII] (also referred to as compound [VIII]) in the same manner as in Production Method 1 to give a compound of the formula [IX] (also referred to as compound [IX]), and the amino-protecting group at R10 of the compound [IX] is eliminated by a method known per se to give a compound of the formula [X] (also referred to as compound [X]), which is then reacted with a compound of the formula [XI] (also referred to as compound [XI]), whereby a compound of the formula [If] (also referred to as compound [If]) is produced.
The reaction of compound [X] with compound [XI] in Production Method 4 is carried out in a solvent that does not adversely influence the reaction in the presence of a base. As the solvent, exemplified are dioxane, acetonitrile, tetrahydrofuran, chloroform, methylene chloride, ethylene chloride, benzene, toluene, xylene, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide and the like; and a mixture thereof. When compound [XI] can be used as a solvent, it can be used as a solvent.
The base used in the reaction of compound [X] with compound [XI] in the Production Method 4 is exemplified, but not particulary limited to, inorganic base such as alkali metal carbonate (e.g., sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate and the like), alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide and the like), metal hydride compound (e.g., sodium hydride, potassium hydride, calcium hydride and the like) and the like; and organic base such as alkali metal alkoxide (e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like) and amines (e.g., triethylamine, diisopropylethylamine and the like) and the like. The base is used in an amount of generally 1-5 mol, preferably 1-3 mol, per 1 mol of compound [X].
In Production Method 4, compound [XI] is used in a proportion of generally 1-5 mol, preferably 1-3 mol, per 1 mol of compound [X].
While the reaction conditions such as reaction temperature and reaction time and the like in the reaction of compound [X] with compound [XI] in the Production Method 4 vary depending on the reagent, solvent and the like to be used in this reaction, the reaction generally proceeds at a temperature of from xe2x88x9230xc2x0 C. to 150xc2x0 C. for 30 min to about a dozen hours. 
wherein R1, R3, A, B and Y are as defined above, R9 is such a group as makes a group of the formula:xe2x80x94CH2xe2x80x94R9 alkyl optionally having a substituent, cycloalkylalkyl, arylalkyl optionally having a substituent, alkenyl optionally having a substituent, alkynyl optionally having a substituent or heterocyclic alkyl optionally having a substituent.
In Production Method 5, compound [Ic] is reacted with a compound of the formula [XII] (also referred to as compound [XII]), whereby a compound of the formula [Ig] (also referred to as compound [Ig]) is produced.
In a group of the formula: xe2x80x94CH2xe2x80x94R9, the xe2x80x9calkyl optionally having a substituentxe2x80x9d, xe2x80x9ccycloalkylalkylxe2x80x9d, xe2x80x9carylalkyl optionally having a substituentxe2x80x9d, xe2x80x9calkenyl optionally having a substituentxe2x80x9d, xe2x80x9calkynyl optionally having a substituentxe2x80x9d and xe2x80x9cheterocyclic alkyl optionally having a substituentxe2x80x9d are as defined for R2. In Production Method 5, compound [Ic] and compound [XII] are condensed in a solvent which does not inhibit the reaction (e.g., water, methanol, ethanol, dioxane, acetonitrile, tetrahydrofuran, chloroform, methylene chloride, ethylene chloride, benzene, toluene, xylene, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, a mixture thereof and the like) in the presence of a reducing agent.
The reducing agent used in the Production Method 5 is not subject to any particular limitation, and is exemplified by metal hydride complex (e.g., lithium aluminum hydride, sodium cyanoborohydride (NaBH3CN), sodium borohydride and the like), borane and the like.
In Production Method 5, compound [XII] is used in an amount of generally 1-5 mol, preferably 1-3 mol, per 1 mol of compound [Ic]. The reducing agent is used in an amount of generally 1-5 mol, preferably 1-3 mol, per 1 mol of compound [Ic].
While the reaction conditions such as reaction temperature and reaction time and the like in Production Method 5 vary with the reagent, solvent and the like to be used in this reaction, the reaction generally proceeds at a temperature of from xe2x88x9230xc2x0 C. to 150xc2x0 C. for 30 min to about a dozen hours.
The heterocyclic compound [I] obtained in the above-mentioned Production Methods 1-5 may be isolated by a conventional method, and, where necessary, purified by a conventional method such as recrystallization, preparative thin-layer chromatography, column chromatography and the like. The compound can be also purified into a salt as necessary.
The heterocyclic compound [I] may be converted to a pharmaceutically acceptable salt thereof by a method known per se.
The pharmaceutical composition comprising the heterocyclic compound [I] or a pharmaceutically acceptable salt thereof of the present invention may contain an additive and the like. As an additive, exemplified are excipient (e.g., starch, lactose, sugar, calcium carbonate, calcium phosphate and the like), binder (e.g., starch, gum arabic, carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose and the like), lubricant (e.g., magnesium stearate, talc and the like), disintegrator (e.g., carboxymethylcellulose calcium, talc and the like), and the like.
The above-mentioned components are mixed to give a preparation for oral administration such as capsule, tablet, powder, granule, dry syrup and the like, or a preparation for parenteral administration such as injection, suppository and the like, according to a method known per se.
While the dose of the heterocyclic compound [I] or a pharmaceutically acceptable salt thereof may vary according to the administration subject, symptom and other factors, when it is orally administered to an adult patient with, for example, diabetes, diabetic complications or hyperlipidemia, the single dose is approximately 1-500 mg/kg body weight, which is administered 1 to 3 times a day.
The heterocyclic compound [I] and a pharmaceutically acceptable salt of the present invention show a superior hypoglycemic action, a blood hypolipidemic action, an insulin resistance-improving action and a PPAR activating action in mammals (human, cattle, horse, dog, cat, rat, mouse, hamster and the like), and are useful as a hypoglycemic agent, a hypolipidemic agent, an insulin resistance improver, a therapeutic agent of diabetes, a therapeutic agent of diabetic complication, a glucose tolerance improver, an anti-atherosclerosis agent, an anti-obesity agent, an antiinflammatory agent, an agent for the prophylaxis or treatment of PPAR-mediated disease and an agent for the prophylaxis or treatment of syndrome X. To be specific, the heterocyclic compound [I] and a pharmaceutically acceptable salt of the present invention are useful for the prophylaxis or treatment of diabetes, diabetic complications, hyperlipidemia, atherosclerosis, hyperglycemia, diseases caused by insulin resistant impaired glucose tolerance, diseases caused by insulin resistance, obesity, inflammation, PPAR-mediated disease and syndrome X.